Fragment-based lead discovery also known as fragment-based drug discovery is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in molecular weight. It is based on identifying small chemical fragments, which may bind only weakly to the biological target, and then growing them or combining them to produce a lead with a higher affinity. FBLD can be compared with high-throughput screening. In HTS, libraries with up to millions of compounds, with molecular weights of around 500 Da, are screened, and nanomolar binding affinities are sought. In contrast, in the early phase of FBLD, libraries with a few thousand compounds with molecular weights of around 200 Da may be screened, and millimolar affinities can be considered useful. FBLD is a technique being used in research for discovering novel potent inhibitors. This methodology could help to design multitarget drugs for multiple diseases. The multitarget inhibitorapproach is based on designing an inhibitor for the multiple targets. This type of drug design opens up new polypharmacological avenues for discovering innovative and effective therapies. Neurodegenerative diseases like Alzheimer’s and Parkinson’s, among others, also show rather complex etiopathologies. Multitarget inhibitors are more appropriate for addressing the complexity of AD and may provide new drugs for controlling the multifactorial nature of AD, stopping its progression.
Library design
In analogy to the rule of five, it has been proposed that ideal fragments should follow the 'rule of three'. Since the fragments have relatively low affinity for their targets, they must have high water solubility so that they can be screened at higher concentrations.
Advantages of screening low molecular weight fragment based libraries over traditional higher molecular weight chemical libraries are several. These include:
More hydrophilic hits in which hydrogen bonding is more likely to contribute to affinity. It is generally much easier to increase affinity by adding hydrophobic groups ; starting with a hydrophilic ligand increases the chances that the final optimized ligand will not be too hydrophobic.
Higher ligand efficiency so that the final optimized ligand will more likely be relatively low in molecular weight.
Since two to three fragments in theory can be combined to form an optimized ligand, screening a fragment library of N compounds is equivalent to screening N2 - N3 compounds in a traditional library.
Fragments are less likely to contain sterically blocking groups that interfere with an otherwise favorable ligand-protein interaction, increasing the combinatorial advantage of a fragment library even further.
